The present invention is directed to lipid nano-pellets with an average particle size of 50 to 1,000 nm, preferably 80 to 800 nm, which can be used as the excipient system for drugs and which are well suited for peroral administration.
Drugs of biologically active substances which are to be applied in a targeted manner at specific sites in a living organism and which avoid rapid elimination comprise a formulation wherein an active substance is bound to specific excipients or enclosed thereby, such that there shall be no premature release of the substance. Following administration, the release of the effective substances as a rule takes place in the gastro-intestinal tract, the drug either breaking up into particles and the effective substance being dissolved by the digestive liquid, or else the effective substance is only dissolved from the intact initial form by diffusion. This process may take place rapidly or delayed in time (retardation). In all cases, the effective substance after the ensuing resorption passes through the liver (first pass effect) where it is metabolized in part or whole, that is, where it is chemically converted and therefore arrives at the target site only in part.
Long ago small particles were developed for the retarded release of effective substances which substances are enclosed therein. The accessory materials required to fabricate such particles, however, are often physiologically unacceptable, or else the manufacturing methods are costly, or again the particle stability is low. Administered perorally, the effective substance is either dissolved from the particle by diffusion in the digestive tract, or it is released by the enzymatic decay of the particle skin. In both cases, however, the resorbed active substance will then again be subjected to the first pass effect in the liver. Such small particles include micro-capsules, nano-capsules and liposomes.
As a rule, microcapsules made from gelatins or cellulose derivatives incur the drawback that a costly method is required for production and that their particle size is in the micron range.
Nano-capsules as a rule are prepared from polyacrylamides and polycyanoacrylates and other synthetic raw materials. These suffer from the drawback of evincing some toxicity and therefore often are unsuitable for human application.
Liposomes are highly ordered phospholipid-based structures of one or more lipid double layers forming a membrane into the gaps of which substances of proper size will be included. Their size depends on the liposomes being multilaminar or smaller, monolaminar types. The liposomes suffer from the drawback that they are rather unstable.
Volkheimer (Adv. in Pharmacol. Chemoth. 14 [1977] pp. 163-187) has shown by means of starch grains that small, solid particles from the intestine can be found unchanged in the blood and urine. This transport phenomenon, termed "persorption", of intact particles through the intestinal wall however is substantially incomplete. Volkheimer assumes that only 1 of 50,000 of the persorbable particles actually is persorbed. In the case of starch this is not surprising because the starch grains have particle diameters for instance of 2 to 10 microns as regards rice starch and 10 to 25 microns for maize starch. Besides, starch evinces strongly hydrophilic properties whereas preferably lipophilic substances are absorbed in the intestine.
It is furthermore known that long-chain fatty acids with chain lengths of more than 12 carbon atoms are routed not to the liver, but preferably to the lymph system and that by means of a special persorption process, called endocytosis, small droplets or solid particles can pass through the intestinal wall and thereupon are routed into the lymph flow.
The object of the invention is thus to provide drug-carrying particles which are small enough to be persorbed and which are adequately lipophilic and physiologically compatible in order to transport the drug they contain in widely unchanged form through the intestine wall. As a result there is achieved an improvement in the availability at the site of action (resorption improvement) for such effective active drug substances which are poorly resorbed in the known perorally administered forms since they are either poorly soluble, not adequately or at all resorbed in the digestive tract, metabolized too rapidly, metabolized too much, or because they are already destroyed by enzymatic or chemical factors in the digestive tract. Such particles should also preferably be solid at room temperature.
In U.S. Pat. No. 4,331,654 (or the corresponding European patent application No. 0042249) a description exists of magnetically detectable, biodegrading water-free drug carrier consisting of lipid particles as excipients for effective substances, which particles are used in intra-arterial injection and have sizes less than 5,000 nm, preferably of an average size of from 1,000-2,000 nm, and which furthermore contain one or more non-toxic surfactants. The lipids used are fatty acids with melting points between 30.degree. and 100.degree. C., in particular saturated fatty acids, alcohols of higher molecular weights, mono-, di- and tri-glyceride inclusive, glycerin esters of the fatty acids, phospholipids, sterols and cerobrosides. The lipid particles melt above 30.degree. C. The cited surfactants are both ionic and non-ionic, such as polyoxyethylenesorbitane monooleate, salts of long-chain aliphatic alcohols, quaternary ammonium salts and lecithin. Inorganic magnetite, which is insoluble in the lipid phase, is used as the magnetically-responsive substance, the particles being prepared by producing a dispersion in water above the lipid melting point, and isolating the solid micro-particles by lyophilization after cooling. A drug substance may be incorporated into the dispersion.